Synthesis of double-stranded, integration-competent DNA in retroviruses proceeds through an RNA/DNA hybrid intermediate, whose (+) RNA genome must be removed to facilitate the second or (+)-strand DNA synthesis. Hybrid hydrolysis is mediated by the C-terminal ribonuclease H(RNase H) domain of the virus-coded reverse transcriptase (RT). In Human Immunodeficiency Virus (HIV), the etiological agent of acquired immunodeficiency syndrome (AIDS), RT is a p66/p51 heterodimer comprised of asymmetrically-organized subunits processed from the 165 kDa gag/pol polyprotein precursor. Abrogating RNase H function was demonstrated almost two decades ago to inhibit enzyme activity in vitro and virus replication in culture. Since these reports, however, there been a paucity of data on clinical trials with small molecule inhibitors, reflecting concerns over their toxicity, selectivity and cellular penetration.
The natural product α-hydroxytropolone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one) was previously demonstrated to potently and specifically inhibit the ribonuclease H(RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, manicol was ineffective in reducing virus replication in culture, most likely due to toxicity caused by inhibition of cellular enzymes.
Therefore, there still exists an unmet need to find improved treatments for HIV infection by providing new retroviral RNase H inhibitors.